title: Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients.
abstract: OBJECTIVE
  To determine the frequency of KCNQ2 mutations in patients with neonatal epileptic encephalopathy (NEE), and to expand the phenotypic spectrum of KCNQ2 epileptic encephalopathy.
  
  
  METHODS
  Eighty-four patients with unexplained NEE were screened for KCNQ2 mutations using classic Sanger sequencing. Clinical data of 6 additional patients with KCNQ2 mutations detected by gene panel were collected. Detailed phenotyping was performed with particular attention to seizure frequency, cognitive outcome, and video-EEG.
  
  
  RESULTS
  In the cohort, we identified 9 different heterozygous de novo KCNQ2 missense mutations in 11 of 84 patients (13%). Two of 6 missense mutations detected by gene panel were recurrent and present in patients of the cohort. Seizures at onset typically consisted of tonic posturing often associated with focal clonic jerking, and were accompanied by apnea with desaturation. One patient diagnosed by gene panel had seizure onset at the age of 5 months. Based on seizure frequency at onset and cognitive outcome, we delineated 3 clinical subgroups, expanding the spectrum of KCNQ2 encephalopathy to patients with moderate intellectual disability and/or infrequent seizures at onset. Recurrent mutations lead to relatively homogenous phenotypes. One patient responded favorably to retigabine; 5 patients had a good response to carbamazepine. In 6 patients, seizures with bradycardia were recorded. One patient died of probable sudden unexpected death in epilepsy.
  
  
  CONCLUSIONS
  KCNQ2 mutations cause approximately 13% of unexplained NEE. Patients present with a wide spectrum of severity and, although rare, infantile epilepsy onset is possible.
authors.affiliation: From the Neurogenetics Group (S.W., R.H., A.S., P.D.J.), Department of Molecular Genetics, VIB, Antwerp; Laboratory of Neurogenetics (S.W., R.H., A.S., P.D.J.), Institute Born-Bunge, University of Antwerp, Belgium; Epilepsy Centre Kempenhaeghe (S.W.), Oosterhout, the Netherlands; Department of Paediatrics (V.I.), University Hospital Centre Zagreb, Croatia; Division of Pediatric Neurology and Metabolism (R.V.C.), Department of Pediatrics, University Hospital Ghent, Belgium; Danish Epilepsy Centre (H.H., R.S.M.), Dianalund; Institute for Regional Health Research (H.H.), University of Southern Denmark, Odense; Department of Child Neurology (S.G.), Juliane Marie Center, Rigshospital, Copenhagen, Denmark; Pediatric Neurology (A.-S.S., B.C.), Department of Neurology (A.-S.S., B.C., P.D.J.), Antwerp University Hospital, Antwerp University, Antwerp, Belgium; Epilepsy Research Centre (S.B.H., S.M., I.S.), Department of Medicine, University of Melbourne, Austin Health, Australia; Great Ormond Street Hospital (C.E.), London; Institute of Genetic Medicine (R.H.), Newcastle University, UK; Child Neurology and Neurorehabilitation Unit (G.C., M.A.), Department of Pediatrics, Central Hospital of Bolzano; Neurology Unit and laboratories (T.P., R.G., C.M.), A. Meyer Children's Hospital, Florence; Child Neuropsychiatry Unit (L.G.), Spedali Civili, Brescia, Italy; Pädiatrie I (K.R., E.H.), Division of Pediatric Neurology, University Hospital Innsbruck, Austria; University Hospital Essen (B.A.), University Duisburg-Essen; Department of Paediatric Neurology and Developmental Medicine (A.B.), University Children's Hospital Tübingen, Eberhard Karls University of Tübingen; Center for Child Neurology (I.B.), Sana Krankenhaus Gerresheim, Düsseldorf; Department of Neuropediatrics (S.S.), Hospital for Children and Adolescents, University of Leipzig, Germany; Department of Neurology (B.S., A.P.), Boston Children's Hospital, Harvard School of Medicine; Department of Biology (B.S.), Brandeis U
authors.forename: Sarah
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authors.lastname: Weckhuysen
authors.forename: Vanja
authors.initials: V
authors.lastname: Ivanovic
authors.forename: Rik
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authors.forename: Helle
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authors.lastname: Møller
authors.forename: Sabine
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authors.lastname: Grønborg
authors.forename: An-Sofie
authors.initials: AS
authors.lastname: Schoonjans
authors.forename: Berten
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authors.lastname: Ceulemans
authors.forename: Sinead B
authors.initials: SB
authors.lastname: Heavin
authors.forename: Christin
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authors.forename: Gianluca
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authors.lastname: Casara
authors.forename: Tiziana
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authors.lastname: Pisano
authors.forename: Lucio
authors.initials: L
authors.lastname: Giordano
authors.forename: Kevin
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authors.lastname: Rostasy
authors.forename: Edda
authors.initials: E
authors.lastname: Haberlandt
authors.forename: Beate
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authors.lastname: Albrecht
authors.forename: Andrea
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authors.lastname: Bevot
authors.forename: Ira
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authors.lastname: Benkel
authors.forename: Steffan
authors.initials: S
authors.lastname: Syrbe
authors.forename: Beth
authors.initials: B
authors.lastname: Sheidley
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.forename: Simone
authors.initials: S
authors.lastname: Mandelstam
authors.forename: Ingrid
authors.initials: I
authors.lastname: Scheffer
authors.forename: Marco
authors.initials: M
authors.lastname: Angriman
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Peter
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authors.lastname: De Jonghe
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D051658:KCNQ2 Potassium Channel / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D013036:Spasms, Infantile / Q000235:genetics*; D014741:Video Recording
chemical_list: D051658:KCNQ2 Potassium Channel